Developmental Toxicity from Perfluoroalkyl Acid and Mercury Co-Exposure in Experimental and Epidemiological Models

• Author / Creator

  Reardon, Anthony John Francis

• Perfluoroalkyl acids (PFAAs) are synthetic contaminants that are widespread in the environment and routinely detected in human blood. Their prevalence raises concerns over their potential adverse implications on human health, especially from exposure during sensitive stages of development (e.g., pregnancy). PFAAs also share common sources of exposure with mercury (Hg) but the combined effects from co-exposure to these contaminants have yet to be elucidated. Here, it was hypothesized that prenatal exposure to PFAAs would result in deficits in offspring neurological development. These effects were demonstrated in offspring using an experimental model of directly dosed pregnant rats and associated effects in humans were examined in children of participants from a prospective birth cohort. It was further hypothesized that associations and effects from prenatal PFAA exposure would be modified when considering the interaction from co-exposure of PFAAs with Hg, and these associated changes in child neurodevelopment are linked to altered maternal thyroid hormones during pregnancy.Pregnant rats exposed perfluorooctane sulfonate (PFOS) and/or methylmercury (MeHg) were used to determine effects on offspring neurodevelopment. Co-exposure to both PFOS and MeHg induced additive effects in newborns that contrasted with combined exposure results in juveniles. In older offspring, individual exposure to PFOS- or MeHg-alone induced significant changes in behaviour that were not evident in control or combined exposure groups, an antagonistic response mirrored by alterations in measured brain metabolites. This is the first investigation to use a target metabolomics platform to explain changes in offspring behaviour from combined maternal exposure to organic contaminants and heavy metals, providing evidence of a chemical interaction between PFOS and MeHg. A longitudinal study design was used to investigate time-dependent associations of PFAAs with thyroid hormones over each trimester of pregnancy and postpartum, considering additional stress of Hg co-exposure in the APrON birth cohort. Perfluorohexane sulfonate (PFHxS) and branched isomers of PFOS were positively associated with TSH, with the strongest associations early in gestation. Higher perfluoroalkyl sulfonate exposures associated with higher TSH and/or lower FT4 are strongly suggested to be risk factors for subclinical maternal hypothyroidism. This was one of the first investigations to observe PFOS isomer-specific associations with maternal thyroid hormones, an important consideration for future studies as these associations may be overlooked when only considering crude measures of ‘total-PFOS’.To evaluate associations with child neurodevelopment, PFAAs collected during the second trimester of pregnancy and interaction with Hg were modeled with child development outcomes at 2-years-old. PFAAs were negatively associated with cognitive and social-emotional development scores. Specific PFOS isomers were associated with child language scores, associations that were determined to be non-linear. Other modeled PFAAs were revealed to be associated with child motor and social-emotional scores only when considering Hg-interaction, suggesting that significance of PFAA-neurodevelopment associations are potentiated by the presence of Hg. This thesis provides evidence of neurodevelopmental toxicity of PFAAs in experimental and epidemiological models. In animals, combined exposure to PFOS and/or MeHg alters the behaviour and brain chemistry of offspring. In humans, prenatal exposure to PFAAs and corresponding isomers disrupt maternal thyroid hormones during pregnancy, exacerbated in women exhibiting thyroid hormone dysregulation, or modified by Hg co-exposure that may explain PFAA-associated changes in child neurodevelopment.

• Subjects / Keywords

  • Perfluoroalkyl acids
  • Developmental Toxicity
  • Chemical Mixtures
  • Toxicology
  • Environmental Epidemiology

• Graduation date

  Spring 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-xq1b-8h27

• License

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